IAS: Investigative Drugs Zero in on HIV Vulnerabilities

SYDNEY, July 24 -- New compounds that seek ways to disrupt mechanisms of the HIV life cycle were outlined here, reflecting an expanding investigative antiviral pipeline.

Among the compounds and investigative agents discussed at a session on new drug development at the International AIDS Society meeting, chaired by Robert Murphy, M.D., of Northwestern, were:

• A series of compounds being developed by Panacos Pharmaceuticals of Gaithersburg, Md., that appears to have the ability to prevent fusion of HIV with its target CD4-positive cell. Another entry inhibitor, injectable enfuvirtide (Fuzeon) is on the market, but the Panacos compounds are designed to be taken orally and to block the entry cascade at a different location.
• A second-generation maturation inhibitor, also being developed by Panacos. The company's first-generation product bevirimat is phase IIB development. The new molecule, PA1050040, has a different resistance profile and is less likely to bind to protein than bevirimat. Phase I trials are under way.
• A series of compounds called dihydroxytropolones that attack the reverse transcriptase enzyme, one of the three key enzymes of the HIV virus. Nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors all attack this facet of the HIV lifestyle.
• Small molecule inhibitors of the interaction of HIV-1 Tat-protein with phosphatase-1 prevent HIV-1 transcription . "We have always suggested that finding inhibitors of tat would be a welcome weapon in the AIDS arsenal," said Dr. Murphy.
• A molecule that prevents dimerization in the protease enzyme, another of the critical enzymes of the virus.

"We need more antiretroviral drugs to fight HIV infection because no matter how good we are, the virus develops resistance as it evolves," commented Robin Isaacs, M.D., executive director of infectious disease and HIV Vaccine Clinical Research at Merck Research Laboratories in Upper Gwynedd, Pa.

Dr. Isaacs, whose company was not involved in the research presented in the discussion session, said, "We are also going to have to have sufficient drugs to give patients options for treatment for 30 or 40 years. We have not yet reached the point where we have the perfect drug in the sense of tolerance and convenience."

He said that development of an oral fusion inhibitor would answer the question of convenience for those taking enfuvirtide who require twice-daily injections.

Karl Salzwedel, Ph.D., director of drug discovery for Panacos, said that the company has three different groups of compounds that are being studied to see which of the fusion inhibitor molecules would make appropriate drug candidates.

"We expect to seek an investigative new drug application with the FDA by the end of this year, and we may begin clinical trials by the end of 2008," he said.

He said that the molecules in development operate in an area that is upstream in the fusion cascade from enfuvirtide.

Dr. Murphy said that most of the compounds discussed in the session "are a long way down the road, but these chemists that have developed the compounds are from very successful groups."